The present invention relates to a method for the preparation of a useful medicine isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate, which is a novel compound not known or not described in the literatures, as a precursor in the preparation thereof.
Isosorbide-5-nitrate is a compound expressed by the formula ##STR1## known for a long time as a metabolic product in a living body of the so-called isosorbide nitrate or isosorbide-2,5-dinitrate having a vasodilatating activity to peripheral veins. It has been recently discovered in the course of the investigations undertaken to elucidate the mechanism for the effectiveness of the latter compound that isosorbide-5-nitrate itself is useful and promising as a therapeutic medicine for several heart troubles due to disorder in coronary arteries such as angina pectoris, mycocardial infarction and the like.
Several methods are known for the preparation of isosorbide-5-nitrate which can be classified into 4 types as a rough classification including:
(1) a method of the nitration of isosorbide, i.e. 1,4:3,6-dianhydrosorbitol, with concentrated nitric acid or acetyl nitrate in a solvent mixture of acetic acid and acetic anhydride disclosed in Canadian Journal of Chemistry, volume 45, page 2191, DE-A No. 2,221,080, U.S. Pat. No. 3,886,186 and Japanese Patent Publication 55-29996;
(2) a method of partial hydrolysis of isosorbide-2,5-dinitrate obtained by the complete nitration of isosorbide disclosed in Organic Magnetic Resonance, volume 3, page 693, EU-A No. 59,664 and Japanese Patent Kokai No. 57-156492;
(3) a method starting from isomannide disclosed in West German Pat. No. 2,903,927, FR-A No. 2,447,933 and Japanese Patent Kokai No. 55-127393; and
(4) a method in which the hydroxyl group at the 5-position of isosorbide is nitrated with the hydroxyl group at the 2-position selectively protected by a suitable protecting group followed by the elimination of the protecting group disclosed in DE-A No. 3,028,873, DE-A No. 3,128,102, EU-A No. 45,076, EU-A No. 57,847, EU-A No. 64,194 and Japanese Patent Kokai No. 57-144288, 57-185286, 58-18385 and 58-18386.
These prior art methods are, however, not quite satisfactory due to the problems and disadvantages in one or more respects. For example, the reaction mixture after the direct nitration of isosorbide according to the above described first method contains 4 compounds including isosorbide-2,5-dinitrate, isosorbide-2-nitrate, isosorbide-5-nitrate as the desired reaction product and the unreacted isosorbide while no efficient method is known for the separation of these components into respective pure forms. In particular, the explosiveness of the dinitrate excludes the possibility of undertaking heating or concentration under reduced pressure of the reaction mixture in the purification of the desired product so that the only possible technique applicable to the purification of the product in this case is the column chromatography. In addition, the reaction of nitration must be performed at a relatively low temperature by taking utmost care for the handling of the nitrating agent when it is explosive and dangerous acetyl nitrate greatly decreasing the productivity of the process. These problems and disadvantages, along with the low yield of about 20% of the desired product based on the theoretical value, hardly afford the practicability of the method of direct nitration.
The second method of the partial hydrolysis of isosorbide-2,5-dinitrate is also quite disadvantageous from the standpoint of practicability because no hydrolyzing agent satisfactory both in the activity and in the selectivity is known. For example, the activity of hydrochloric acid as a hydrolyzing agent is low so that the reaction of hydrolysis can be completed only by taking an unduly long time. The hydrolysis reaction of the dinitrate by use of a hydrazine derivative suffers from the large amount of isosorbide-2-nitrate formed as a byproduct so that the reaction mixture after completion of the hydrolysis reaction must be purified by the techniques of column chromatography in order to isolate the desired product.
The third method from isomannide as the starting material has a problem of the low availability of isomannide in comparison with isosorbide. In addition, the intermediate with tosylation of the hydroxyl group at the 2-position must be further converted into a benzoate. The nitration of the hydroxyl group at the 5-position can proceed only by use of the explosive and dangerous acetyl nitrate. It is of course that the benzoate group at the 2-position must be finally eliminated. Therefore, the practical and industrial value of this method is greatly decreased when the complicated and long sequence of the steps is taken into consideration.
The last of the above described prior art methods is also disadvantageous from the standpoint of industrialization due to the long and complicated sequence of steps including the protection of the hydroxyl group at the 2-position with a protecting group followed by the elimination thereof after the nitration of the hydroxyl group at the 5-position. In addition, the low selectivity of the reaction in this method limits the practical applicability of the method to the industrial production because the reaction mixture contains large amounts of byproducts which can be separated from the desired product only by the column chromatographic techniques if not to mention the relatively low yield of the desired product.